Tocilizumab vs Azathioprine in Neuromyelitis Optica Spectrum Disorders

Phase 2

Completed

• Conditions: Neuromyelitis Optica; Neuromyelitis Optica Spectrum Disorders
• Interventions: Drug: Tocilizumab Injection; Drug: Azathioprine

• Registration Number: NCT03350633
• Lead Sponsor: Tianjin Medical University General Hospital

Brief Summary

In neuromyelitis optica spectrum disorder (NMOSD),interleukin-6 (IL-6) may play an important role in facilitating plasma cells to produce pathological aquaporin 4 (AQP4) autoantibody. Inhibition of IL-6 signaling pathway by Tocilizumab (ACTEMRA®), a humanized monoclonal antibody may have shown beneficial clinical effects in a few patients with NMOSD.

Larger scale clincial trials may be needed to observe its efficacy and safety. Here, by choosing azathioprine, one of the most frequently used medication in case of relapses, the investigators compare the safety and efficacy of tocilizumab in preventing NMOSD attacks.

Detailed Description

The investigators primarily aim to observe the time to first relapse from initiation of tocilizumab or azathioprine treatment. The proportion of participants who experience relapse-free in one year follow-up will be compared.

The secondary outcomes are to determine: The safety profile of tocilizumab and azathioprine in participants with NMO and whether tocilizumab improves visual function, Expanded Disability Status Scale (EDSS), et al.

Study Timeline

• Study Start: 2017-11-01
• Study First Submitted: 2017-11-10
• Study First Submitted QC: 2017-11-17
• Study First Posted: 2017-11-22
• Primary Completion: 2019-09-01
• Study Completion: 2019-09-01
• Status Verified: 2019-10
• Last Update Submitted: 2019-10-22
• Last Update Posted: 2019-10-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 118

Inclusion Criteria

1. Male or female patients ≥ 18 years old
2. Diagnosis of NMO or NMO spectrum disorder
3. Clinical evidence of at least 2 relapses in last 12 months or 3 relapses in the last 24 months
4. Able and willing to give written informed consent and comply with the requirements of the study protocol.
5. EDSS <= 7.5 (8 in special circumstances)
6. Men and women of reproductive potential must agree to use a highly effective method of birth control from screening to 6 months after final dose of the investigational product.

Exclusion Criteria

1. Current evidence or known history of clinically significant infection (Herpes simplex virus, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus,human immunodeficiency virus, Hepatitis viruses, Syphilis, etc)
2. Pregnant, breastfeeding, or child-bearing potential during the course of the study
3. Patients will not participate in any other clinical therapeutic study or will not have participated in any other experimental treatment study within 30 days of screening
4. Participation in another interventional trial within the last 3 months
5. Heart or kidney insufficiency
6. Tumor disease currently or within last 5 years
7. Clinically relevant liver, kidney or bone marrow function disorder
8. Intolerance of azathioprine or previous relapses on azathioprine treatment
9. Receipt of rituximab or any experimental B-cell depleting agent within 6 months prior screening and B-cells below the lower limit of normal.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tocilizumab	Tocilizumab Injection	Tocilizumab Injection (ACTEMRA®) , a IL-6 receptor blockade
Azathioprine	Azathioprine	Imuran

Primary Outcome Measures

Name	Time	Method
Time to first relapse	From baseline to one year after	An acute attack was defined as a new neurological worsening lasting for at least 24 hours and occurring more than 30 days after the previous attack.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 24 Weeks	From baseline to 60 weeks	Disability improvement was assessed only for the subgroup of participants with a baseline EDSS score of \>= 2.0. It was defined as a reduction in EDSS score of: A) \>=1.0 from the baseline EDSS score when the baseline score was \>=2 and \<=5.5 B) \>= 0.5 when the baseline EDSS score \> 5.5. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death).
Change in Low-contrast Letter Acuity (LCLA) at Week 60	From baseline to 60 weeks	Adjusted mean change in LCLA at Week 60 from baseline as determined by 2.5% low contrast Sloan letter charts, adjusted for the baseline LCLA value.
Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI)	From baseline to 60 weeks	The total number of new and/or enlarging T2 lesions for all participants in the treatment group was calculated as the sum of the individual number of lesions at Weeks 12, 36, and 60
Determination of serum cytokines	From baseline to 60 weeks	Compare serum cytokines before and one year after initial intervention
Worsening in EDSS	Worsening from baseline in EDSS to 60 weeks	The Expanded Disability Status Scale (EDSS) is a rating system that is frequently used for classifying and standardizing the severity and progression. EDSS ranges from 0 to 10.
Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks	From baseline to 60 weeks	Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) \>=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (\<=) 5.5 B) \>=0.5 point from the baseline EDSS score when the baseline score was \>5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 12 weeks after the initial documentation of neurological worsening. Participants who had initial disability progression with no confirmatory EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment.
Change in High-contrast Letter Acuity (HCLA) at Week 60	From baseline to 60 weeks	Adjusted mean change in HCLA at Week 60 from baseline as determined by 100% high contrast Sloan letter charts, adjusted for the baseline HCLA value.
Determination of serum immunoglobulins	From baseline to 60 weeks	Compare immunoglobulins before and one year after initial intervention
Proportion of patients who experience relapse-free	From baseline to 60 weeks	To record whether the patients had no relapses in the follow-ups
Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks	From baseline to 60 weeks	Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) \>=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (\<=) 5.5 B) \>=0.5 point from the baseline EDSS score when the baseline score was \>5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death). Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 24 weeks after the initial documentation of neurological worsening. Participants who had initial disability progression with no confirmatory EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment.
Counts of peripheral blood B cell subsets	From baseline to 60 weeks	Compare peripheral blood plasma cells before and one year after initial intervention
Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 12 Weeks	From baseline to 60 weeks	Disability improvement was assessed only for the subgroup of participants with a baseline EDSS score of \>= 2.0. It was defined as a reduction in EDSS score of: A) \>=1.0 from the baseline EDSS score when the baseline score was \>=2 and \<=5.5 B) \>= 0.5 when the baseline EDSS score \> 5.5. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death).
Percentage change in SD-OCT Average Retinal Ganglion Cell Layer/Inner Plexiform Retinal Layer (RGCL/IPL) at Week 60	From baseline to 60 weeks	Adjusted mean change in thicknesses of the RGCL/IPL at Week 60 for the affected eye from the baseline as determined by segmentation of SD-OCT.
Overall safety and tolerability of tocilizumab or azathioprine	From baseline to 60 weeks	Adverse events related to tocilizumab or azathioprine are recorded.
Percentage Change in Spectral-domain Optical Coherence Tomography (SD-OCT) Average Retinal Nerve Fiber Layer (RNFL) Thickness at Week 60	From baseline to 60 weeks	Adjusted mean percentage change in thickness of the RNFL at Week 60 for the affected eye from the baseline as determined by SD-OCT.
Number of Participants with Adverse Events as a Measure of Safety and Tolerability	From baseline to 60 weeks	Treatment-emergent adverse events, treatment-emergent serious adverse events (TESAEs), including laboratory measurements as well as their changes or shift from baseline over time
Determination of serum AQP4 antibodies	From baseline to 60 weeks	Compare serum AQP4-ab titers before and one year after initial intervention

Trial Locations

Locations (1)

Tianjin Medical University General Hospital; 🇨🇳 Tianjin, Tianjin, China